A Personalized Approach - Putting the Squeeze on Mesothelioma

Background:Malignant Pleural Mesothelioma (MPM) is an asbestos induced, infiltrative, aggressive and incurable cancer that originates in the pleural lining of the lung. The cancer results in high levels of fibrosis and pleural effusions. Genetic profiling of MPM tumours has unveiled specific but limited set of common loss of function mutations in tumor suppressors. These include prominent mutations within Hippo pathway members and in the deubiquitinase BAP1 (1). MPM patients have a bleak outlook: life expectancy after diagnosis is 1-1.5 years. Current treatment options are not effective and in general can be considered palliative care. Consequently, there is an urgent need for new and enhanced experimental models that replicate the disease in order for patients to access tailored treatment approaches. To this end we will leverage our recently developed and unique isogenic in vitro experimental model (2) to directly determine the tumour stroma’s role and mechanical forces in mesothelioma. 

Our cellular models also contain patient derived cellular models including primary cells and organoids. These cellular models are compatible with high content imaging and a microfluidic setup combined with digital homographic imaging (3) that allow us to directly assess how mesothelioma in patients with distinct mutations differ. Targeting loss of tumour suppressors as in mesothelioma is challenging, and we will therefore seek to identify new therapeutic targets, through a targeted CRISPR screen in order to identify new potential therapeutic targets (4). We will carry out proteomics on prioritized KO targets. This combined will give insights into synthetic lethality, dysregulated protein complexes and networks. We expect these will give us new therapeutic targets, that we will directly assess by combinatorial genetic and chemical targeting approaches. In this advanced setup utilizing cellular disease models that represent the heterogeneity among patients, we can mimic critical disease relevant in vivo scenarios thereby evaluate cancerous cells drug sensitivities in scalable high content imaging compatible model systems. Experimental cellular models are in place. These cellular models combined with the unique experimental setups provides us with an opportunity to understand how mesothelioma patients differ, and discover new precision medicine therapeutic targets, that we anticipate will develop into new stratified treatment opportunities.